51_01

RECURRENT TUMORS

Marie E. Taylor
Carlos A. Perez
Seymour H. Levitt

Principles & Practice of Radiation Oncology, Third Edition; edited by
C. A. Perez and L. W. Brady. Lippincott-Raven Publishers, Philadelphia
Copyright 1997. Chapter 51, pp 1415-1448.

Locally advanced breast cancer is defined by 1992 American Joint
Committee (AJC) staging criteria as stage IIIa and IIIb disease. Stage
IV disease also includes ipsilateral supraclavicular nodal involvement
in the absence of other sites of distant disease. The 1992 AJC staging
system is shown in Chapter 50. Any of the following clinical or
pathologic findings at presentation represents locally advanced
carcinoma staging: tumor size greater than 5 cm with clinically or
pathologically positive axillary lymph nodes; tumor of any size with
direct extension to ribs, intercostal muscles, or skin; edema
(including peau d'orange) and/or ulceration of the skin of the breast,
or satellite skin nodules confined to the same breast; inflammatory
carcinoma (T4d); metastases to ipsilateral axillary lymph nodes fixed
to one another or to other structures; metastases to the ipsilateral
internal mammary lymph nodes; and metastases to the ipsilateral
supraclavicular lymph nodes.

The proportion of patients presenting with locally advanced breast
cancer varies. Haagensen [ref: 105] described 11.6% of cases as having
locally advanced breast cancer. Tumor Registry data at Washington
University Medical Center indicate that approximately 6% of all newly
diagnosed clinically staged breast cases from 1990 through 1994 were
stage III (40% stage IIIa, 60% stage IIIb). When pathologic staging
criteria were used, the proportion of breast cancer cases at our
institution was 8% DCIS; 48% stage I; 35% stage II; 6% stage III; and
3% stage IV. Patients with stage III disease have 55% to 60% survival
at 5 years and 35% to 40% at 10 years. Optimal therapy for these
patients aims to maximize overall and disease-free survival and to
prevent the often serious morbidity of locally recurrent disease.

Natural History

Locally Advanced (T3 and T4) Tumors

Locally advanced breast cancer may evolve from a mass to an
infiltration of the deep lymphatics of dermis, causing edema of the
skin. More pronounced edema (peau d'orange) usually indicates that the
superficial lymphatics as well as the deeper ones are involved. Later
in the course of disease, fixation of the skin over the tumor and
localized redness occur, followed by ulceration and infiltration of
the overlying skin. Skin retraction may be caused by tumor invasion of
Cooper's ligament. Further indications of extensive involvement are
the appearance of satellite nodules and carcinoma en cuirasse, in
which the skin becomes plaquelike and yellowish, red, or gray. [ref:
105]

Lymphatic spread to the axillary, internal mammary, and
supraclavicular lymph nodes frequently occurs. The supraclavicular
lymph nodes most often become involved after high axillary or internal
mammary nodes are involved. However, if there is a large tumor burden
within the breast or if skin in the upper half of the breast is
involved, direct spread to the supraclavicular lymph nodes can occur.
The most common initial sites of hematogenous spread, in order, are
bone, lung, and pleura [ref: 54]; initial involvement of the liver and
brain can occur but is less commonly seen. [ref: 32,256]

Inflammatory Carcinoma

Inflammatory carcinoma of the breast is defined by both clinical and
pathologic criteria. The clinical definition is the presence of
warmth, erythema, and peau d'orange in the involved breast. The
alternative pathologic criterion is the presence of tumor emboli in
dermal lymphatics. [ref: 75,147] Inflammatory carcinoma of the breast
is a biologically aggressive tumor that presents a major challenge to
all oncologists. [ref: 17] Henderson and McBride [ref: 111] emphasized
the difference between primary and secondary inflammatory carcinoma of
the breast according to Haagensen's criteria. [ref: 105] Primary
lesions have acute presentation with erythema over a significant
portion of the breast and concomitant edema and ridging. Often, there
is no palpable mass. This description is most consistent with a
diagnosis originally described by Taylor and Metzler. [ref: 236] In
contrast, secondary inflammatory carcinoma of the breast is more
characteristically a neglected, locally advanced breast cancer with
inflammatory-like changes resulting from underlying necrosis or
ulceration. Making the distinction between these two lesions is often
difficult; dermal lymphatic invasion is present in both, suggesting
that the mechanism for the inflammatory skin changes is similar in
both groups.

Historically, inflammatory breast cancer has been characterized by a
high rate of locoregional recurrence after a mastectomy and also by
the rapid development of metastatic disease.

Clinical Presentation

Patients present with a heterogeneous collection of tumor and nodal
findings. Symptoms include local or regional pain, bleeding,
paresthesia, and paresis. A common presentation includes clinically
palpable findings in the breast, axilla, and supraclavicular region,
skin changes, and possibly arm edema or findings of brachial
plexopathy.

Diagnostic Workup

Physical examination must give special attention to documenting the
locoregional extent of disease and carefully checking potential sites
of hematogenous spread. Areas of erythema, edema, subtle subcutaneous
infiltration, and small subcutaneous nodules are easily missed and
could lead to marginal failures if not taken into account when
irradiation fields are planned. Fixation to the pectoralis muscle or
fascia can be determined by assessing the mobility of the mass with
the pectoralis muscle relaxed and contracted. Regional lymph nodes
should be thoroughly evaluated by careful clinical examination and by
chest computed tomography (CT) if radiographic evaluation of the
internal mammary lymph nodes appears indicated.

Laboratory studies should include a complete blood cell count and
serum chemistry profile with full liver function tests. In the event
of anemia, leukopenia, or thrombocytopenia, morphologic evaluation is
indicated, and bone marrow biopsy is necessary. Radiographic studies
should include chest x-ray, bone scan, and plain radiographs of
symptomatic regions or suspicious areas of increased uptake on bone
scans. Bone scans are generally recommended for patients with stage
III or IV disease even if the alkaline phosphatase level is normal
[ref: 79]; about 35% of patients with stage III cancer have an
abnormal bone scan. [ref: 13,35,48] If the patient has abnormal liver
function values, a CT scan of the abdomen should be obtained. If there
are any neurologic symptoms suggestive of cerebral metastases, a
contrast-enhanced CT scan or gadolinium-enhanced magnetic resonance
imaging (MRI) scan of the brain should be obtained.
Gadolinium-enhanced MRI is the preferred study if leptomeningeal
carcinomatosis is suspected.

Prognostic Factors

Prognostic factors can be intrinsic (related to the initial inherent
condition of the tumor itself, such as lymph node involvement and
histology) or extrinsic (related to the type and adequacy of therapy).
Donegan and colleagues [ref: 69] noted that the following extrinsic
factors were most frequently related to local recurrence.

Gross Characteristics of the Primary Tumor

Larger tumors, more diffuse tumors, and presence of edema are
associated with increased local recurrence. [ref: 69]

Histologic Tumor Grade

Incidence of local recurrence increases with more poorly
differentiated tumors.

Meyer and co-workers [ref: 160] showed a significant correlation of
the thymidine labeling index (TLI), an indication of growth fraction,
with survival rate. TLI below the median of 4.55 carries a 20%
probability of relapse at 4 years, in contrast to 52% probability of
failure with TLI above the median. Sylvestrini and associates [ref:
232] concluded that pretreatment TLI does not correlate with tumor
response to primary chemotherapy. However, it provides information on
the course of the disease, in that a high TLI significantly predicts a
higher progression rate after completion of therapy, a shorter time to
disease progression, and poorer probability of 4-year survival in
comparison with low TLI. This information can allow selection of cases
requiring more aggressive therapy.

Hormonal Receptors

Patients without hormonal receptors have a significantly lower
survival rate and are not likely to respond to hormonal therapy. [ref:
156,257] Conflicting reports have been published on the correlation
between the presence or absence of hormone receptors and chemotherapy
response. [ref: 124,143]

Fisher and colleagues [ref: 84] found that the most significant
pathologic features related to estrogen receptor (ER) and progesterone
receptor (PR) positivity and concordance (ER+PR+, ER-PR-) were
well-differentiated nuclear and histologic grade, slight or absent
tumor lymphoid infiltration, slight or absent necrosis, and moderate
or marked elastica. All of these factors were directly or indirectly
related to tumor differentiation. Disease-free survival decreased from
concordant ER+PR+ to discordant receptors (ER+PR- or ER-PR+), with the
worst prognosis in patients with concordant ER-PR-.

Likewise, McGuire and colleagues [ref: 49,157] observed a strong
correlation between hormone receptor content, percent of cells in S
phase of the cell cycle and aneuploidy and suggested that these
measurements in concert may identify a subset of patients who are at
increased risk for recurrence. Arnarlov and colleagues [ref: 7]
reported that aneuploidy correlated significantly with histologic
grade, axillary perinodal growth, and disease-free survival.

Chevallier and associates [ref: 43] noted that ER and PR have their
own prognostic value and should be considered among other classic
prognostic factors.

DNA Index

Von Rosen and co-workers [ref: 251] found nuclear DNA distribution
patterns to be of prognostic value in node-negative patients but not
in node-positive patients. Fallenius and associates [ref: 77] also
noted that tumors with normal DNA content (diploid or euploid) had a
better prognosis. Dressler and colleagues [ref: 72] noted that
aneuploidy and high S-phase fraction correlated with absence of
steroid receptors.

Involvement of Axillary Nodes by Tumor

Local recurrence developed in 26% of patients with involved axillary
nodes, compared with 6.5% of patients without it; the greater the
number of nodes involved, the more likely the local recurrence. Fisher
and associates [ref: 83] also reported diminishing survival rate with
greater number of metastatic axillary lymph nodes. Baldursson [ref:
15] described 5-year relapse-free survival rates of 91% for pN0, 50%
for pN1, and 19% for pN2-3. The 5-year survival rates for the groups
were 86%, 53%, and 30%, respectively.

Response to Chemotherapy

Tumor and axillary nodal response to neoadjuvant chemotherapy has been
shown to be an indicator for disease-free survival. [ref:
29,154,201,241,245] McCready and co-workers, [ref: 154] in 136
patients with locally advanced breast cancer who received preoperative
chemotherapy followed by mastectomy and axillary dissection, noted on
univariate analysis that number of metastatic lymph nodes, clinical
tumor stage at presentation, clinical and pathologic response, and
menopausal status were significant variables directly associated with
overall and disease-free survival. When evaluated by multivariate
regression, surgical lymph node staging was the most important factor
for disease-free survival. Borger and associates [ref: 29] found
primary tumor size and clinical nodal status to be independent
prognostic factors for locoregional tumor control; patients whose
mastectomy specimen had no gross residual disease had a 93% survival
at 5 years, compared with 30% in patients with less marked response to
therapy (P < 0.01).

General Management

This heterogeneous group of breast cancers includes large primary
tumors, tumors with fixed ipsilateral axillary nodes (N2), tumors with
ipsilateral supraclavicular or infraclavicular nodes, and tumors
producing arm edema. [ref: 1,92] In general, life expectancy is
primarily determined by the high probability (about 80%) that these
patients will develop bloodborne metastasis. [ref: 16,184] Because of
the compelling need for systemic therapy, chemotherapy has assumed a
principal role in most treatment trials of patients with locally
advanced and inflammatory breast cancer. Radiation and surgery each
have important roles to optimize locoregional tumor control.

General management for patients with locally advanced and inflammatory
breast carcinoma is typically defined by operability. There is a
consensus that all patients with technically resectable disease should
have surgery. Historically, borderline resectable or unresectable
locally advanced breast cancers have been treated by radiation therapy
alone. More recently, the use of chemotherapy or hormonal treatment
(or both) before surgical resection and irradiation has played a more
prominent role. In about 80% of cases, borderline inoperable or
inoperable tumors treated with chemotherapy regress sufficiently to
become operable. [ref: 114,179] Chemotherapy may also sensitize the
tumor to local irradiation. Indicators for postoperative radiation
therapy include tumor size greater than 5 cm in diameter; skin,
fascial, or skeletal muscle invasion; poorly differentiated tumors;
lymphatic permeation, four or more positive axillary nodes; matted
nodes at presentation; gross extracapsular tumor extension; and
inadequate surgical margins. Relative total doses of radiation are
determined by the bulk of the residual tumor (primary and/or nodal)
and the adequacy of the surgical margins.

In inflammatory breast carcinoma, chemotherapy followed by mastectomy
and irradiation provides the best tumor control and survival data.
[ref: 176]

Radiation Therapy Techniques

Irradiation of the Inoperable Breast

Patients whose breast cancer is technically inoperable should receive
radiation therapy to the breast, supraclavicular nodes, and axillary
nodes. Treatment of the ipsilateral internal mammary lymph nodes may
be indicated for medial chest wall involvement or if there is clinical
or radiographic involvement of the internal mammary node chain. The
breast is treated with photons through tangential fields with borders
similar to those used in early breast cancer, ensuring that all
potential tumor-bearing tissues are adequately covered. Treatment of
the intact breast and draining lymphatics in patients with advanced
breast cancers presents several technical challenges:

1. Homogeneous irradiation of the breast tissue despite its
half-oblate geometric shape.

2. Adequate skin and dermal dose. In contrast to early breast cancer,
in which there is no clinical need to treat the skin and underlying
dermis, in advanced breast cancer gross or subclinical skin or dermal
involvement is frequently present and must be treated.

3. Precise matching between the plane of the inferior border of the
supraclavicular field and the plane of the superior border of the
medial and lateral breast tangential fields. With the sharp beam edges
of the modern linear accelerator, inadequate matching may result in a
thin cold plane of tissue that may harbor a nidus for recurrence or a
thin plane of matchline fibrosis.

4. Minimal beam divergence into the lung from the medial and lateral
breast tangential fields and minimal dose as low as possible to the
opposite breast from the lateral breast tangential.

5. Adequate coverage of the internal mammary nodes. Inclusion of the
internal mammary nodes in the breast tangential fields often results
in irradiation of too much lung. On the other hand, use of a separate
single anterior internal mammary field that matches the medial border
of the medial breast tangential field produces a cold wedge of breast
tissue that is often unacceptable; this cold wedge may harbor gross or
subclinical deposits of cancer cells.

Adequate Skin and Dermal Dose

Adequate skin and dermal dose is of particular importance.
Technically, it is easily achieved by adding bolus over the entire
breast using a box-shaped bolus that provides an adequate skin dose as
well as homogeneous irradiation of the breast tissue.

The more difficult clinical issue is determining the necessary number
of bolus treatments, given the limits of normal skin tolerance.
Empiric clinical experience has been to use bolus in 40% to 60% of
treatments, either consecutively or every other day. If a separate
internal mammary field is used, it is very important to ensure
adequate coverage of the skin at the junction with the medial
tangential portal.

Irradiation of the Chest Wall

Irradiation of the chest wall after mastectomy can be accomplished
with tangential photon fields, as used in the treatment of the intact
breast, or with appositional electron beams. If tangential photon
fields are used, the technical challenges are similar to those
encountered in treatment of the intact breast. Adequate skin and
dermal dose are achieved by adding bolus over the entire field for one
third of the treatments and adding bolus to the scar alone for an
additional third of the treatments. In treatment of chest wall
recurrences, bolus to the entire field should be used for about one
third of the treatments and bolus with a generous margin around the
recurrence for most, if not all, of the remaining treatments.

Several electron-beam techniques can be used as an alternative to
tangential photon treatment; the simplest is a single appositional
field using 9- to 12-MeV electrons. Bolus should be used for part of
the treatment to increase the surface dose beyond the 80% to 90%
typically given with these beams and to minimize the lung dose.

The difficulty with a single appositional electron field is poor
lateral coverage (Fig. 51-1); a single, medially angled electron field
may be added to boost the depth coverage in the lateral region. [ref:
122] Otherwise, use of more sophisticated electron arc [ref:
133,134,158,174] or pseudoarc technique [ref: 31] may be required.
Electron arc therapy is a technically demanding and time-consuming
treatment. Field shaping requires the use of custom lead strips or a
Cerrobend cast placed on the patient's skin. It is often unappreciated
that the surface dose in the electron arc technique is much lower than
that for the single electron beam of the same energy, and the
effective depth of coverage is less. Use of bolus to bring up the
surface dose becomes mandatory.

Field Borders

Anatomic landmarks defining the field borders for treatment of
breast/chest wall tangentials, supraclavicular nodes, internal mammary
nodes, and axilla are similar to those used in the treatment of early
breast cancer (Fig. 51-2A, Fig. 51-2B, and Fig. 51-2C).

Examples of various field arrangements for irradiation of the chest
wall and regional lymphatics are shown in Figure 51-3. Table 51-1
describes the advantages and disadvantages of the four techniques. The
dose distributions for two tangential fields to the chest wall and
internal mammary portal are illustrated in Figure 51-4.

Matchline Technique

Many methods have been used to achieve an ideal match of the anterior
oblique supraclavicular field caudal edge and the cephalad edge of the
tangential field. A nondivergent supraclavicular field edge is always
achieved by blocking the inferior half of the field. A variety of
methods achieve a nondivergent edge from the tangential beams,
including blocking and table angulation in combination with collimator
angulation. Multiple reports describe techniques using custom
Cerrobend blocking for the cephalad tangential border. [ref:
47,117,135,212] Another technique uses a gravity orbited block to
achieve a nondivergent edge independent of gantry angle. [ref: 228]
Use of a rotatable half-beam block is another matching technique.
[ref: 213,247]

The Mallinckrodt Institute of Radiology Radiation Oncology Center has
used a matchline technique adapted from Lichter and co-workers [ref:
142] that mathematically yields nondivergent edges for the tangential
cephalad border by calculation of appropriate table and collimator
angle combinations depending on gantry angle. Both adaptations are
needed to avoid the trapezoid effect of beam divergence that is
prominent for gantry angles other than directly lateral. This method
has been effective, and field edge feathering has been unnecessary;
however, it requires a great deal of technical time and multiple
calculations at the time of simulation. Precision in day-to-day setup
requires careful technical attention. The matchline technique was
recently changed to employ asymmetric jaws to beam split all portals
along the central axis plane. This technique uses one isocenter to
treat the opposed tangential breast field, the supraclavicular portal,
and the posterior axillary field. With the precision matchline, the
patient does not have to move in any direction on the treatment couch.
Details of this technique have been described. [ref: 126] Dosimetric
studies show that asymmetric jaws provide nearly equivalent field edge
definition and superior absorption in comparison with Cerrobend
blocks. The use of one isocenter results in a reduction of room
treatment time by a factor of two. A composite portal film, which
includes the medial tangential and supraclavicular portals, shows a
perfect matchline for all portals (Fig. 51-5A). Similar composite
portal films, taken with the previous method of geometric matching
with collimator and table angulation, exhibit slight overlap or
underdose regions in many cases (Fig. 51-5B).

Doses

A total dose of 50 to 60 Gy in 1.8- to 2-Gy daily fractions should be
given to the entire breast or chest wall. If no surgery is feasible,
the breast should be boosted an additional 10 to 25 Gy with external
irradiation (electrons or photons) using shrinking fields or with an
**192Ir implant to a total dose of 75 to 80 Gy. The boost dose is
determined by the volume of residual disease. The internal mammary
nodes, supraclavicular fossa, and axillary nodal areas should receive
45 to 50 Gy over 5 to 6 weeks if no macroscopic tumor is present. Any
gross nodal disease should then be boosted with an additional 10 to 15
Gy; an appositional electron-beam field may be used.

Treatment Results

Locally Advanced Breast Carcinoma

Technically Resectable Locally Advanced Breast Cancer

Three published randomized prospective trials [ref: 103,125,172,220]
specifically studied the efficacy of post-mastectomy irradiation in
locally advanced patients. Spangenberg and associates [ref: 220]
randomly assigned 131 patients with technically resectable stage III
breast cancer to receive either radiation therapy and single-agent
chemotherapy (cyclophosphamide) or multiagent chemotherapy alone. The
multiagent chemotherapy regimen included CMF (cyclophosphamide,
methotrexate, and 5-fluorouracil [5-FU]) and vinblastine. The 5-year
relapse-free survival rate was 40% for patients in the former group
and 27% in the latter group. This difference was not statistically
significant.

Papaioannou and co-workers [ref: 172] treated patients with induction
chemotherapy (cyclophosphamide, doxorubicin, vincristine,
methotrexate, and 5-FU with tamoxifen or oophorectomy) followed by
surgery; 205 patients were randomly assigned to receive or not receive
radiation therapy. Both groups received postoperative chemotherapy
(cyclophosphamide, doxorubicin, vincristine, methotrexate, 5-FU, and
tamoxifen). The relapse-free survival was 79% with irradiation,
compared with 73% without it. This difference was not statistically
significant. The trial was flawed by 78 exclusions from the analysis.

In the Helsinki University Stage III Trial, 120 patients with operable
stage III breast cancer were randomly assigned to receive
postmastectomy irradiation, postmastectomy chemotherapy, or a
combination of both. [ref: 103,125] The first 60 patients assigned to
each arm also received levamisole. The incidence of distant metastasis
among patients receiving chemotherapy was 25% in the
chemotherapy-alone arm and 28% in the combination arm, compared with
70% among patients treated with irradiation alone. The incidence of
local failure among patients receiving radiation therapy was 20% in
irradiation-alone arm and 8% in the combination arm, compared with 58%
among those treated with chemotherapy alone. The reduction of both
distant metastases and local failures in patients receiving both
adjuvant chemotherapy and irradiation led to a statistically
significant improvement in overall freedom from relapse and survival
(Fig. 51-6). This important study strongly suggests that in patients
at high risk for locoregional failure, postoperative irradiation added
to mastectomy and adjuvant chemotherapy can have a significant impact
on survival as well as on locoregional tumor control.

Borderline Resectable Or Unresectable Locally
Advanced Breast Cancer

Radiation Therapy Alone

Five-year survival rates for series reporting results with radiation
therapy alone range from 10% to 25%. [ref: 16,33,44,87,102,195,242]
With moderate doses of radiation, local tumor control rates of 35% to
65% can be expected. [ref: 10,16,33,95,102] Doses of 75 to 100 Gy can
yield local control rates of 70% to 100% (Table 51-2) [ref:
3,58,87,168,231] but carry with them a significant risk of soft
tissue, rib, and lung injury. [ref: 221]

Table 51-3 shows local tumor control correlated with radiation dose by
use of mastectomy versus no mastectomy, with or without systemic
therapy. [ref: 177] Noted is the general trend of improved local tumor
control with systemic therapy. Local failure, with or without systemic
therapy in the absence of mastectomy, remains a large portion of
breast recurrence despite higher doses of radiation.

Radiation Therapy Alone Versus Irradiation
Followed by Chemotherapy

The high rates of distant failure in patients with borderline
resectable or unresectable breast cancer highlight the need for
adequate systemic therapy in these patients. [ref: 16,184] Several
published studies have suggested an improved freedom from relapse in
patients treated with chemotherapy and irradiation, compared with
historic results in patients treated with irradiation alone. [ref:
30,39,63,64,78,175,192,196]

Two randomized trials compared radiation therapy alone or combined
with chemotherapy. Between 1977 and 1980, 118 patients at the
Netherlands Cancer Institute were randomly assigned to receive
irradiation alone, irradiation followed by 12 cycles of CMF, or
irradiation followed by alternating cycles of AV (Adriamycin and
vincristine) and CMF. Patients in both chemotherapy arms also received
tamoxifen. The 5-year survival rate was 37% in all arms of the study.
No statistically significant difference in overall freedom from
relapse or locoregional recurrence occurred among any of the arms.
[ref: 203]

Between 1978 and 1985, 231 patients with locally advanced
noninflammatory carcinoma of the breast were randomly assigned to
receive either radiation therapy alone or irradiation plus CMF
chemotherapy; the randomization included both low- and high-dose CMF.
Parenthetically, 120 patients had technically resectable lesions and
underwent mastectomy before randomization. For the combined group of
technically operable and inoperable patients, a significant
improvement in freedom from relapse was seen in premenopausal patients
receiving chemotherapy. No difference occurred in overall survival.
For postmenopausal women, no difference occurred in either freedom
from relapse or overall survival. [ref: 65]

Chemotherapy Followed by Irradiation Versus
Chemotherapy Followed by Surgery

In two published prospective trials, patients with tumors made
resectable with initial chemotherapy were randomly assigned to either
mastectomy or breast irradiation; one study was from the National
Cancer Institute of Milan [ref: 63,246] and the other from the Cancer
and Leukemia Group B (CALGB) study group. [ref: 179] Neither trial
showed any statistically significant difference in freedom from
relapse or survival rate between the surgery and irradiation arms.

Chemotherapy, Surgery, and Radiation Therapy

Extrapolating from the superiority of the triple-modality arm
(surgery, radiation therapy, and chemotherapy) in the Helsinki trial
for operable stage III breast cancer, [ref: 103,125] it may be
persuasively argued that triple-modality treatment is most likely to
yield the best results in marginally unresectable or unresectable
advanced breast cancer. Several single-arm protocols also suggest that
this may be the case. [ref: 14,34,172,205] As yet, no randomized
prospective trial has compared such triple-modality treatment with
lesser treatment.

Perez and co-workers [ref: 177] described the retrospective outcome of
treatment for 281 women with locally advanced breast carcinoma. Median
follow-up was 6.2 years. Thirty-five patients were treated with
irradiation alone, 33 with irradiation and adjuvant chemotherapy, 81
with mastectomy and irradiation, and 32 with mastectomy, irradiation,
and chemotherapy (triple-modality). Disease-free survival correlated
with T stage and N stage is shown in Figure 51-7A. Cause-specific
survival paralleled disease-free survival in these groups.
Locoregional tumor control at 5 years 31%, 54%, 80%, and 91% in the
four groups, respectively (P < 0.0001) (Fig. 51-7B). More than 80% of
locoregional failures occurred within 3 years of initial treatment.
Systemic therapy and/or irradiation given before mastectomy yielded
better locoregional tumor control, disease-free survival, and
cause-specific survival, although these results were not statistically
significant (P = 0.1). The addition of any type of surgery versus no
surgery improved both local tumor control (P < 0.0001) and
disease-free survival (P = 0.0002).

Patterns of failure correlated with treatment modality are shown in
Figure 51-8; mastectomy substantially decreased locoregional
recurrence, but distant metastases were a major component of failure.
Noted is the lower overall proportion of total failure with
trimodality therapy, compared with single or bimodality treatment.
When locoregional tumor control and disease-free survival were
correlated with type of systemic therapy, no statistically significant
difference was found between chemotherapy plus hormones, chemotherapy
alone, or hormones alone. However, there was a statistically
significant improvement in locoregional tumor control and in
disease-free survival with use of any type of systemic therapy,
compared with no systemic therapy (P = 0.022 and P = 0.0013,
respectively). With respect to timing of adjuvant systemic therapy, a
suggested improvement in both locoregional tumor control and
disease-free survival was seen with neoadjuvant chemotherapy versus
adjuvant chemotherapy after irradiation and/or mastectomy, although
these differences were not statistically significant (P = 0.35 and
0.22, respectively). The authors concluded that trimodality therapy is
superior to any other treatment combination and that additional
clinical trials are needed to further define the roles and optimal
uses of the various treatment modalities.

Breast Conservation Therapy for Patients with
Locally Advanced Operable Breast Cancer

The advantages of neoadjuvant chemotherapy have been emphasized by
many authors [ref: 89,120,144,225,229]; these include reduced size of
the primary tumor and regional lymph nodes and eradication of distant
micrometastases. Jacquillat and associates [ref: 120] reported a 100%
complete tumor response in 98 patients after neoadjuvant chemotherapy
plus hyperfractionated irradiation (23 Gy in four fractions) and an
interstitial implant (22 to 30 Gy); the breast was preserved in most
patients, and only 13% locoregional relapse was reported. However,
follow-up was short at the time of the report, and long-term
complications were not assessed.

Bonadonna and colleagues [ref: 27] described results in 165 women with
breast cancer (tumors 3 to < 7 cm). Candidates for mastectomy were
distributed in groups of 33 patients to receive three or four cycles
of neoadjuvant CMF, CAF (cyclophosphamide, doxorubicin, and 5-FU), or
FEC (5-FU, epirubicin and cyclophosphamide). Tumor regression to less
than 3 cm was demonstrated in 127 (81%) of 157 patients who were
subjected to wide local tumor excision (quadrantectomy), allowing
preservation of the breast. Postoperative irradiation to the breast
(60 Gy in 6 weeks) was started 4 to 6 weeks after surgery. Among 75
women with minimum follow-up of 12 months, only 1 had failed in the
breast and 11 at other sites (including 3 in the ipsilateral
supraclavicular nodes).

Singletary and associates, [ref: 214] in 143 patients receiving
neoadjuvant chemotherapy, identified by review of mastectomy specimens
33 patients (23%) who were candidates for breast conservation therapy.
The observed incidence of multiple-quadrant involvement for the
following factors was found: persistent skin edema plus other factors,
65%; tumor greater than 4 cm with other factors, 56%, intramammary
lymphatic invasion with other factors, 20%; and multicentric tumor
plus other factors, 16%. The authors reported that persistent skin
edema was an ominous sign; 25% of patients with this finding
experienced chest wall recurrence after mastectomy and adjuvant
irradiation.

Touboul and colleagues [ref: 240] reported on 97 patients with locally
advanced nonmetastatic, noninflammatory breast cancer treated with
neoadjuvant chemotherapy (four courses of doxorubicin, vincristine,
cyclophosphamide, and 5-FU) followed by preoperative irradiation to
the breast and regional lymph nodes (45 Gy) and a fifth course of
chemotherapy after irradiation. In 37 patients with residual tumor
larger than 3 cm, mastectomy and axillary dissection were performed;
the other 60 patients were treated with conservation therapy. In 33
patients, there was complete tumor regression, and no surgery was
done; an additional boost of 20 Gy was delivered at the 85% level of
the basal dose with an interstitial **192Ir boost of 25 to 30 Gy in 15
fractions with external irradiation. Twenty-seven patients who had
residual mass 3 cm or smaller were treated with wide tumor excision
and axillary dissection followed by a boost of 20 Gy with **192Ir
brachytherapy. After completion of local therapy, all patients
received a sixth course of chemotherapy. Maintenance adjuvant
chemotherapy without an anthracycline was prescribed (12 monthly
cycles). The 5-year locoregional relapse rates were 16% with
irradiation alone, 16% with wide tumor excision and irradiation, and
5.4% with mastectomy (P = 0.04). The 5- and 10-year overall survival
rates were 80% and 69%, respectively, and disease-free survival rates
were 73% and 61%, respectively. There was no significant influence of
local treatment on outcome. Arm lymphedema was noted in 12.5% of
patients treated with axillary dissection and in 3% without axillary
dissection. Cosmetic results were satisfactory in 79% of patients
after wide excision and irradiation and in 71% of patients treated
with irradiation alone.

At the present time, breast conservation therapy for patients with
locally advanced breast carcinoma may be an option in selected cases.
However, longer-term follow-up is needed before this approach may be
accepted as standard of care.

Inflammatory Breast Cancer

The Institut Gustave-Roussy [ref: 192] retrospectively compared the
results of treatment with irradiation and hormonal manipulation (group
C: 60 patients treated from 1973 to 1975); induction AVM (doxorubicin,
vincristine, and methotrexate) plus radiation therapy, and maintenance
VCF (vincristine, cyclophosphamide, and 5-FU) (group A: 91 patients
treated from 1976 to 1990); and induction AVCMF (doxorubicin,
vincristine, cyclophosphamide, methotrexate, and 5-FU) plus radiation
therapy, and maintenance VCF (group B: 79 patients treated from 1980
to 1982). The 4-year disease-free survival rates were 15% for group C,
32% for group A, and 54% for those receiving the most intense
chemotherapy regimen, group B. The corresponding survival rates at 4
years were 42%, 53%, and 74%, respectively. The authors concluded that
a combination of intensive induction chemotherapy and maintenance
chemotherapy can improve both freedom from relapse and survival
compared with irradiation alone.

At Washington University, 179 patients received radiation therapy as
part of the treatment of nonmetastatic inflammatory breast cancer.
[ref: 176] All patients had histologic confirmation of carcinoma of
the breast; 22 patients had only pathologic evidence of dermal
lymphatic permeation, 56 had clinical findings only, and in 98 the
diagnosis was based on both clinical and pathologic findings. There
was no significant difference in cause-specific survival based on the
use of clinical or pathologic criteria for diagnosis. Patients were
treated with four different regimens: 33 were treated with irradiation
alone, 35 with a combination of irradiation and chemotherapy, 25 with
irradiation plus surgery, and 86 with trimodality therapy.
Triple-modality therapy consisted of three cycles of CAF and total or
modified radical mastectomy as feasible. This was followed by chest
wall and regional lymphatic irradiation (50 Gy in 5.5 to 6 weeks) in
combination with cyclophosphamide and 5-FU. Patients with positive
hormonal receptors were treated with hormonal therapy. If the lesion
was unresectable after three cycles of neoadjuvant chemotherapy or if
there was tumor progression, irradiation to the intact breast and
regional lymphatics was given and was followed, if possible, by
mastectomy. Patients with unresectable lesions received additional
doses of radiation to 75 Gy to the tumor volume.

The 5-year disease-free survival rate was 40% for patients treated
with trimodality therapy, 24% for those receiving irradiation and
surgery, and 6% for those treated with irradiation alone or
irradiation combined with chemotherapy without surgical treatment. The
corresponding 10-year disease-free survival rates were 35%, 24%, and
0%, respectively (P < 0.01) (Fig. 51-9). Clearly superior locoregional
tumor control was observed in patients undergoing surgical procedures:
79% with three modalities, 76% with irradiation and surgery, and only
30% with irradiation alone or combined with chemotherapy (P < 0.01).
Distant metastases occurred in 57% of the group treated with
triple-modality therapy, 60% of those treated with irradiation and
surgery, and 85% of those treated with irradiation alone or combined
with chemotherapy. There was no significant correlation between type
of mastectomy or dose of radiation and locoregional tumor control and
survival. Significant morbidity of trimodality therapy (10%), although
somewhat higher than that seen with other modalities (3.2%), was
considered acceptable (P = 0.1). Trimodality had a less pronounced,
although still statistically significant, impact on disease-free
survival and cause-specific survival. The authors found no
statistically significant difference in locoregional tumor control or
disease-free survival based on the sequence of triple modality therapy
(neoadjuvant therapy versus chemotherapy, radiation therapy, and
surgery; surgery, radiation therapy, and chemotherapy; or surgery,
chemotherapy, and radiation therapy). The addition of any
chemotherapy, with or without the use of hormonal therapy, was shown
to result in a statistically significant improvement in locoregional
control (P = 0.01) and a strong although not statistically significant
trend for improved disease-free survival (P = 0.08) (Fig. 51-10A and
Fig. 51-10B). Clearly, prospective randomized studies documenting
therapy outcome by treatment sequence would be helpful.

Postoperative Radiation Therapy in Stage I and II Breast Cancer

Postoperative radiation therapy is recommended for patients with
lesions larger than 5 cm in diameter; any skin, fascial, or skeletal
muscle involvement; poorly differentiated tumors; positive or very
close surgical margins; lymphatic permeation; matted lymph nodes; four
or more positive axillary lymph nodes; or gross extracapsular tumor
extension. It appears that adjuvant irradiation can be effectively
given before, concurrent with, or after chemotherapy.